The bone is an important part of the body that structurally supports muscles, organs and soft tissues of the human body, surround and protects internal organs from external impact, and stores calcium or other essential minerals such as phosphorus or magnesium in the body.
The bone is composed of osteoblasts, osteocytes, osteoclasts. Among them, the osteoblasts are derived from mesenchymal stem cells which can differentiate into chondrocytes, myocytes and adipocytes and play a role in forming bone tissues through the proliferation, bone matrix formation and calcification stages. And, the osteoclasts are involved in bone resorption.
The old bone of an adult is removed by the osteoclasts and new bone is created by the osteoblasts through the bone remodeling process of repeated bone resorption and creation. For example, the osteoblasts maintain the homeostasis of bone metabolism as they regulate the differentiation of the osteoclasts responsible for bone resorption by secreting RANKL (receptor activator of nuclear factor-κB ligand) and its decoy receptor OPG (osteoprotegerin).
A disruption of the homeostasis of bone metabolism due to a specific cause results in metabolic bone diseases such as osteoporosis, osteodystrophy, fracture, etc.
Osteoporosis, which is a representative metabolic bone disease, refers to a condition of increased risk of fracture due to increased bone weakness where bone mineral density decreases below 2.5 or T-score (standard deviation from the average bone mass of normal adults) decreases below −2.5. Osteoporosis occurs frequently in postmenopausal women. It is known that the bone matrix is decreased with aging and adipocytes occupying the void inhibit the function and differentiation of the bone-creating osteoblasts and promote the function and differentiation of the osteoclasts responsible for bone resorption by secreting inflammatory cytokines. A severe reduction in bone density can easily result in fracture even with a small impact. Although osteoporosis itself has no symptoms, fractures, especially the fracture of the thighbone, vertebral column, etc., caused by bone weakness make it impossible to live a healthy life and, consequently, cause 15% of death in the elderly.
Osteodystrophy is a disease of the bone caused by chronic renal failure, etc. It occurs due to congenitally abnormal kidney function and can lead to death unless dialysis is performed. This bone disease is called renal osteodystrophy. Bone diseases associated with the osteodystrophy include osteomalacia, osteitis fibrosa, etc.
Calcium supplements are recommended for the treatment or prevention of the metabolic bone diseases. For postmenopausal women, vitamin D or hormone drugs such as estrogen or calcitonin are recommended. In addition, bisphosphonate-based bone resorption inhibitors such as Fosamax (alendronate) and Actonel (risedronate), which inhibit osteoclasts and induces their death, are mainly used.
However, it is known that, although the calcium supplements prevent the decrease in bone mass caused by bone resorption by suppressing the secretion of parathyroid hormone, the effect varies greatly among individuals. Also, although the hormone drugs increase bone density, they are reported to have side effects such as breast cancer, myocardial infarction, venous thrombosis, etc. (Nelson, H. D et al., JAMA, 288: 872-881, 2002; Lemay, A., J. Obstet. Bynaecol. Can., 24: 711-7152-3). As for the bisphosphonate drugs, the cases of necrosis of the jaw, severe atrial fibrillation, atrophy of bone or joint or pain of the skeletal muscle are reported (Coleman R E., Br J Cancer, 98: 1736-1740 (2008).
In addition, although the existing drugs for treating or preventing metabolic bone diseases have the pharmacological activity of preventing further bone loss, they do not provide the effect of restoring decreased bone mass to the original state.
The inventors of the present disclosure have identified that a newly synthesized novel compound can treat and prevent metabolic bone diseases or obesity through regulation of osteoblast and adipocyte differentiation and have completed the present disclosure.